Table 3.
Summary of adverse events by weight band and dolutegravir dose and formulation
| Total | 3 kg to <6 kg (<6 months) | 3 kg to <6 kg (≥6 months) | 6 kg to <10 kg | 10 kg to <14 kg | 14 kg to <20 kg | 14 kg to <20 kg | 20 kg to <25 kg | Non-per protocol | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Dose* | .. | 5 mg | 10 mg | 15 mg | 20 mg | 25 mg | 25 mg | 30 mg | .. | |
| Formulation | .. | DT | DT | DT | DT | FCT | DT | DT | .. | |
| Number of participants | 71 | 8 | 5 | 28 | 18 | 25 | 19 | 2 | 14 | |
| Follow-up, weeks† | ||||||||||
| Median | 24·0 (24·0–24·0) | 11·3 (6·6–12·0) | 10·9 (4·0–12·0) | 15·6 (12·0–24·0) | 24·0 (12·0–24·0) | 24·0 (24·0–24·0) | 24·0 (23·6–24·0) | 11·3 (0·4–22·1) | 5·4 (1·9–11·7) | |
| Range | 1·0–48·0 | 1·3–12·0 | 1·0–20·1 | 0·0–24·0 | 0·0–24·0 | 12·7–24·0 | 0·6–24·0 | 0·4–22·1 | 0·1–23·4 | |
| Number of participants with a serious adverse event | 11/71 (15%) | 2/8 (25%) | 2/5 (40%) | 3/28 (11%) | 1/18 (6%) | 2/25 (8%) | 0 | 0 | 1/14 (7%) | |
| Number of serious adverse events‡ | 13 | 2 | 2 | 3 | 1 | 2 | 0 | 0 | 3 | |
| Haematological | 1 (8%) | 1 (50%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Infectious disease | 9 (69%) | 1 (50%) | 1 (50%) | 2 (67%) | 1 (100%) | 2 (100%) | 0 | 0 | 2 (67%) | |
| Non-HIV-related deaths (traumatic) | 1 (8%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33%)§ | |
| Systemic | 2 (15%) | 0 | 1 (50%)¶ | 1 (33%) | 0 | 0 | 0 | 0 | 0 | |
| Number of participants with a grade ≥3 event | 19/71 (27%) | 2/8 (25%) | 2/5 (40%) | 5/28 (18%) | 4/18 (22%) | 3/25 (12%) | 1/19 (5%) | 0 | 2/14 (14%) | |
| Number of grade ≥3 events‖ | 29 | 3 | 3 | 7 | 8 | 3 | 1 | 0 | 4 | |
| Biochemical | 2 (7%) | 0 | 0 | 0 | 2 (25%) | 0 | 0 | 0 | 0 | |
| Haematological | 7 (24%) | 2 (67%) | 0 | 1 (14%) | 3 (38%) | 0 | 0 | 0 | 1 (25%) | |
| Infectious disease | 15 (52%) | 1 (33%) | 1 (33%) | 5 (71%) | 3 (38%) | 2 (67%) | 1 (100%)** | 0 | 2 (50%) | |
| Nervous system | 1 (3%) | 0 | 0 | 0 | 0 | 1 (33%) | 0 | 0 | 0 | |
| Non-HIV-related deaths (traumatic) | 1 (3%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (25%)§ | |
| Systemic | 3 (10%) | 0 | 2 (67%)¶ | 1 (14%) | 0 | 0 | 0 | 0 | 0 | |
| Person-years | 38·4 | 1·4 | 0·9 | 8·9 | 6·3 | 11·2 | 7·2 | 0·4 | 2·1 | |
| Grade ≥3 event rate per 100 person-years (95% CI) | 76 (51–108) | 214 (44–625) | 326 (67–953) | 79 (32–163) | 127 (55–251) | 27 (6–79) | 14 (0–77) | 0 (0–0) | 194 (53–495) | |
Data are n, median (IQR), n/N (%), or n (%), unless otherwise specified. 13 children participated in the first (25 mg film-coated tablet) and second (25 mg dispersible tablet) pharmacokinetic substudies (14 kg to <20 kg) with no overlap; one child was exposed to and completed pharmacokinetic profiles on dispersible 15 mg while weighing 6 kg to less than <10 kg (12 weeks safety follow-up; two grade ≥3 events reported as components of the same clinical serious adverse event) and 20 mg while weighing 10 kg to less than <14 kg (24 weeks safety follow-up; no events reported); one child was exposed to and completed pharmacokinetic profiles on dispersible 10 mg (non-per-protocol dose; 3 weeks safety follow-up) and 5 mg (24 weeks safety follow-up) while weighing 3 kg to less than 6 kg and being younger than 6 months (no events reported); one child was exposed to and completed pharmacokinetic profiles on 20 mg film-coated tables (non-per-protocol dose; 21 weeks safety follow-up) and 25 mg dispersible tablet (24 weeks safety follow-up) while weighing 14 kg to less than 20 kg (no events reported). DT=dispersible tablet. FCT=film-coated tablet.
Exposed to dolutegravir once per day or twice per day with rifampicin: one child weighing 3 kg to less than 6 kg and being younger than 6 months was exposed to 10 mg dispersible dolutegravir twice per day (non-per-protocol dose); three children weighing 6 kg to less than 10 kg were exposed to 15 mg dispersible dolutegravir twice per day; two children weighing 10 kg to less than 14 kg were exposed to 20 mg dispersible dolutegravir twice per day; one child weighing 14 kg to less than 20 kg was exposed to 25 mg dispersible dolutegravir twice per day; and two children weighing 14 kg to less than 20 kg were exposed to 25 mg film-coated dolutegravir twice per day.
Follow-up based on time-updated dose: dose changes were primarily the result of increased weight and moving to the intended pharmacokinetic dose in the second pharmacokinetic substudy.
Serious adverse events are analysed as episodes, with all components of the same clinical serious adverse events presented as one episode.
One child died due to a traumatic accident.
One child died due to kwashiorkor.
For grade 3 or higher clinical and laboratory adverse events, each component of the same episode is analysed as a separate event.
One event (ie, hepatitis A virus infection) resulted in discontinuation of dolutegravir.